This invention is a pharmaceutical composition that is effective in the treatment of hepatitis. The composition can be used to treat viral infections, notably hepatitis, including hepatitis C virus (HCV) and hepatitis B virus (HBV). The composition comprises one or more (5-aryl-1,2,4-thiadiazol)-3-yl-urea or (5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivatives in combination with interferon and/or ribavirin. Methods of treating viral infections are also disclosed.
HIV and other viral infections such as hepatitis are a leading cause of death.
Hepatitis is a disease of the human liver. It is manifested with inflammation of the liver and is usually caused by viral infections and sometimes from toxic agents. Hepatitis may progress to liver cirrhosis, liver cancer, and eventually death. Several viruses such as hepatitis A, B, C, D, E and G are known to cause various types of viral hepatitis. Among them, HBV and HCV are the most serious. HBV is a DNA virus with avirion size of 42 nm. HCV is a RNA virus with a virion size of 30-60 nm. See D. S. Chen, J. Formos. Med. Assoc., 95(1), 6-12 (1996).
Hepatitis C infects 4 to 5 times the number of people infected with HIV. Hepatitis C is difficult to treat and it is estimated that there are 500 million people infected with it worldwide (about 15 time those infected with HIV). No effective immunization is currently available, and hepatitis C (HCV) can only be controlled by other preventive measures such as improvement in hygiene and sanitary conditions and interrupting the route of transmission. At present, the only acceptable treatment for chronic hepatitis C is interferon which requires at least six (6) months of treatment. Interferon can inhibit viral replication in infected cells and also improve liver function in some people. Treatment with interferon however has limited long term efficacy with a response rate about 25%.
Hepatitis B virus (HBV) infection can lead to a wide spectrum of liver injury. Moreover, chronic hepatitis B infection has been linked to the subsequent development of hepatocellular carcinoma, a major cause of death. Current prevention of HBV infection is a hepatitis B vaccination which is safe and effective. However, vaccination is not effective in treating those already infected (i.e., carriers and patients). Many drugs have been used in treating chronic hepatitis B and none have been proven to be effective, except interferon.
Treatment of HCV and HBV with interferon has limited success and has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
Because the interferon therapy has limited efficacy and frequent adverse effects, a more effective regimen is needed.
In the present invention it has been discovered that the combination of (5-aryl-1,2,4-thiadiazol)-3-yl-urea or (5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative in combination with interferon works synergistically for the treatment of hepatitis C virus, hepatitis B virus, and other hepatitis infections. Moreover, these same (5-aryl-1,2,4-thiadiazol)-3-yl-urea or (5-aryl-1,2,4-thiadiazol)-3-yl thiourea reduce the level of toxicity of ribavirin, another drug used in the treatment of hepatitis, particularly hepatitis C.
A pharmaceutical composition for administering, to animals, and in particular warm-blooded animals and humans, infected with a hepatitis virus is disclosed. The composition comprises a therapeutically effective amount of interferon or ribavirin or a combination of interferon and ribavirin with an anti-viral compound selected from the group consisting of a (5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative or a (5-aryl-1,2,4-thiadiazoly)-3-yl urea derivative having the formula: 
wherein X is oxygen or sulfur; R is hydrogen or alkyl having from 1-3 carbons; n is 0-4; and R1 is independently selected from the group consisting of hydrogen, alkyl having from 1 to 7 carbon atoms, chloro, bromo, fluoro, oxychloro, and alkoxy having the formula xe2x80x94O(CH2)yCH3 wherein y is from 1 to 6; or a pharmaceutical addition salt or a prodrug thereof, and optionally a pharmaceutical carrier.
Preferred anti-viral compositions comprise a therapeutically effective amount of the anti-viral compound (5-phenyl-1,2,4-thiadiazoly)-3-yl thiourea, which has the formula: 
The compositions can be used to treat hepatitis C, hepatitis B, herpes simplex and other viral infections.
More specifically, this invention provides an anti-viral composition comprising a pharmaceutical carrier, interferon or ribavirin or a combination of interferon and ribavirin and a (5-aryl-1,2,4-thiadiazol)-3-yl thiourea derivative or (5-phenyl-1,2,4-thiadiazol)-3-yl urea derivative as defined herein along with a method for treating viral infections for example, hepatitis C, hepatitis B, or other hepatitis infections. The preferred interferon is interferon-alpha.
The compositions can be used in conjunction with other treatments. The route of administration is the same as for other medical treatments. The drug can be given daily or from 1 to 4 times a week.